Methods and benzamide compositions for producing cns depressant and hypotensive activity

ABSTRACT

SIMULTANEOUSLY ACTING CENTRAL NERVOUS SYSTEM (CNS) DEPRESSANT AND/OR HYPOTENSIVE PHARMACEUTICAL COMPOSITIONS COMPRISING EFFECTIVE AMOUNTS OF COMPOUNDS OF THE FORMULA:   (NC-(CH2)X-N(-R)-CO-),A,B,C-BENZENE   WHEREIN A, B, AND C ARE SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, LOWER ALKYL, LOWER ALKOXY, AND HALOGEN RADICALS AT LEAST ONE OF WHICH IS AN ALKOXY OR A HALOGEN RADICAL; WHEREIN X IS A WHOLE NUMBER FROM ONE TO THREE, AND WHEREIN R IS SELECTED FROM THE GROUP CONSISTING OF CYCLOALIPHATIC RADICALS CONTAINING BETWEEN THREE AND SEVEN CARBON ATOMS, TOGETHER WITH CARRIERS THEREFOR, AND THE METHODS FOR ADMINISTERING SAID COMPOUNDS.

United States PatentOflice Patented Apr. 30, 1974 3 808,315 METHODS ANDBENZ AMIDE COMPOSITIONS FOR PRODUCING CNS DEPRESSANT AND HYPO- TENSIVEACTIVITY these compositions to small animals to produce these etfects.

The compositions of this invention are unit dosage forms, such astablet, capsule,.elixir, sterile solution, suspension, etc., containinga therapeutically effective amount g' g gf g fi 982% Road 5 of abenzamide having the general formula: No Drawing. Continuation-impart ofapplication Ser. No. 6 CH2) 180,206, Sept. 13, 1971, now abandoned,which is a division of application Ser. No. 822,029, May's, 1969, B Nnow Patent No. 3,660,461. This application Feb. 28, 10 R 1973, Ser. No.336,415 Us Cl A611 27/00 17 Claims wherein A, B, and C may be mono-,di-, or tri-fluoro-, chloro-, bromo-, iodo-, methoxy, or ethoxy-radicalsand may be monoor di-rnethyl, or ethyl-radicals, but pref- ABSTRACT OFTHE DISCLOSURE erably chloroor methoxyradicals substituted in theSimultaneously acting central nervous system (CNS) 0111105 m P -P butPfeferably in the depressant and/or hypotensive pharmaceutical composiiP -P the P y the tions comprising effective amounts of compounds of the-T 9Y Y the benlamlde y f r l I prise a cyanomethyl-, ethyl-, orpropyl-radical, but pref- A 20 erably the cyanoethyl-radical while the Rradical may 0 )CHm-CN comprise a tri-, quatra-, penta-, hexa-, orhepta-cycloali- B g phatic radical, preferably cyclohexyl radical, whichtogether with the haloor methoxy-radicals on the phenyl 3 ring of thebenzamide confers the proper physico-chemical properties on thesecompounds which are necessary for wherein A, B, and C are selected fromthe group conslstmaximal .activity in the animals tesmi Although thehydrogen lower alkyl, Lower alkoxy and halogen cyanoethyl-radical ispreferred, the N-cyanopropyl-radical radfcals at of whlch IS an alkoxyor a halogen also is good, but the N-cyanomethyl is less elfective, andTadlcal; 9 15 a Whole number from one i f those N-cyanoalkyl radicals offour or more carbon atoms and h i R Selected 9 the group conslstmg ofproduce no significant depressant action in any practical cycloaliphatlcradicals contammg between three and seven dosages carbon atoms f f f"earners therefor and the These benzamides were prepared by themodification of methods for admmlstermg Sald compoundstheSchotten-Baumann Reaction according to the following equation: RELATEDAPPLICATION. /CH1CHzCN This application is a continuation-impart ofWilliam D. Iii-@0001 Roll copending application Ser. No. 180,206 filedSept. 13, 1971, now abandoned, which is a division of application NaOHSer. NO., 822,029, filed May 5, 1969, now US. Pat. l No. 3,660,461,issued May 2, 1972. 011% O CHZcHgC/N BACKGROUND OF THE INVENTION RAlthough similar N-cyanoalkyl benzamides are known, no similar ones Werefound which had either, not to mention both, the CNS depressant andhypotensive effects of applicants compounds. For example; the Crovettiet al. Herein an acyl halide was reacted with an N-(2-cyano- U.'S. Pat.No. 3,457,294 patented July 22, 1969 is for antialkyl)-cycloalkylaminein the presence of sodium hydroxbacterial, antifungal and antiprotozoalactivity, the Purside and chloroform at room temperature and agitateduntil glove US. Pat. No. 2,927,126 patented Mar. 1, 1960 is theexothermic reaction was complete. The chloroform for a biocide, and theSaxon Pat. No. 3,172,869 patented layer was then washed with Water,dried with anhydrous Mar. 9, 1965 is for a plasticizer. sodium sulfateand evaporated in a vacuum to produce 2 Although similar N-cycloalkylbenzamides are known, viscous yellow oil which crystallized on standingfor a they only had biocide or CNS depressant effects, and none periodof several weeks. This crude product was then rehad hypotensiveactivity. crystallized from aqueous ethanol to give the pure newcompounds of this invention, which were tested for com- SUMMARY OF THEINVENTION position and physical properties. The results of some of Thisinvention comprises pharmaceutical compositions these tests on thepreferred N-cyclohexyl-N-cyanoethylcontaining various benzamides havingnovel depressant methoxyand chlorobenzamides are shown in the followandhypotensive activity and methods of administering 6O ing Table I:

TABLE I Phenyl ring b y Melting ab s g'ia t ign if aiai iiiib a i c fsgsubstltuted above point Example number radical process C.) Ultravioletdata C=O ON C H C H The activity of these benzamide compounds was testedby dissolving them in propylene glycol and parenterally injecting theresulting solutions into small animals such as rats and mice in dosagesof two and of four milligrams per kilogram of weight of the animalinjected. The depressant or stimulatory effects of the new compoundswere determined in mice with actophotometers which measure the totalmovements of a single animal each thirty minute interval over a two hourperiod, and the mean count for each period for twelve animals for eachcompound was recorded. The direct blood pressure measurements for thesenew compounds were conducted in eight Wistar rats for each compound,which rats were under urethan anesthesia, 1.2 g./ kg. i.p., with amercury monometer connected to the carotid artery. The solutions ofthese new compounds were injected via the femoral vein. Indirect bloodpressure measurements were conducted in normotensive Wistar rats using aphotoelectric tensometer.

The results of these pharmacological tests for the new compounds listedin Table I above are shown in the following two Tables II and III for 4mg./kg. and 2 mg./kg. doses, respectively, the latter or smaller doseshaving no significant eifect on the blood pressure:

TABLE II [At dosage 4 mg./kg. in mice] Relative depres- Compound sentaction on Relative of Example central nervous hypotensive number system(CNS) action I l l l i H i l l l i k. i..

I I l J JIl I II F TABLE III [At dosage 2 mg./kg. in mice] Relativestimulation of The pharmaceutical compositions of this invention arecomposed of these benzamides incorporated in a non-toxic liquid or solidpharmaceutical carrier or excipient. Thus, simple propylene glycolsolutions of the active ingredients have been found suitable, however,the active ingredients may be incorporated in pharmaceutical carrierforms, such as tablets or capsules, which may contain other nontoxicmaterials such as fillers or diluents, namely: lactose or sucrose, andmay contain a binding agent such as glucose, gum acacia, gelatin, starchpaste, etc. Furthermore, they may contain lubricants, such as magnesiumstearate, talc, etc., as well as such disintegrating agents as cornstarch, microcrystalline cellulose, etc. The active ingredients may alsobe incorporated into injectable solutions which may contain othernon-toxic materials including: solvents, such as propylene glycol, waterfor injection, etc., and preservatives, such as benzyl alcohol, etc.

The unit dosage forms are prepared by standard formulation methods suchas by granulating and tableting, by mixing with a carrier and fillinginto hard gelatin capsules; by dissolving or suspending in a suitablesterile parenteral vehicle; or by dissolving in an aqueous vehicle foran oral liquid dosage form. a

The unit dosage forms will contain a sufficient amount of activeingredient to provide effective central nervous system depressant and/orhypotensive activity with 'correspondingly minimal toxic side effects.

A unit dose range of from approximately 10-150 mg. provides depressantand/or hypotensive activity with minimal side reactions. Such unit dosesare administered 1-4 times daily. For calculating the amounts of activeingredients in the claimed unit dosage forms, it is often convenient touse milligrams of the active compounds per kilogram of the weight of theanimal to which they are administered, depending on the activity of theactive ingredient together with the size and pharmacology of the hostanimal. In such claimed unit dosages, the active compound will bepresent in approximately 05-10 mg./ kg. but preferably 1-5 mg./kg.amounts.

The following examples are designed to explain the methods ofpreparation and administration of the compounds of this invention, butit is to be understood that they are not to limit the scope of thisinvention:

Example 1 N cyclohexyl-N-cyanoethyl-p-methoxybenzamide was prepared byshaking a mixture of 15 milliliters ofchlOroform, 0.01 mole ofN-(Z-cyanoethyl) cyclohexylamine, 60 milliliters of 5% sodium hydroxide,and 0.01 mole of p-chloro-acyl chloride in a separator at roomtemperature until the exothermic action was complete. The chloroformlayer was washed with water, dried with anhydrous sodium sulfate, andevaporated in a vacuum to produce a viscous yellow oil whichcrystallized on standing for a period of several weeks. These crudecrystals were then re-crystallized from aqueous ethanol to form the pureN- cyclohexyl-N-cyanoethyl-p-methoxy-benzamide sampleof this example.

This sample was then tested according to the Table I above in which thecarbon and hydrogen content or percentages were obtained with a Colemancarbon-hydrogen analyzer. The melting point was determined by using aMettler FP-l melting and boiling point apparatus. The infraredabsorption spectra were obtained with a Perkin- Elmer Model 137-Bspectrophotometer, and the ultraviolet data were obtained with a Bauschand Lomb Spectronic 600 Spectrophotometer.

The oral administration of four milligrams per kilogram of this Example1 compound dissolved in propylene glycol resulted in a significantreduction in thespontaneous motor activity of the mice and rats as wellas causing a simultaneous drop in blood pressure (see Table II above).Ataxia was clearly discernible in the animal at elevated dosages such asfor example ten milligrams.

per kilogram, and a rat responded even more dramatically to suchelevated dosages, by assuming a cataleptoid pos ture. Slightly lowerdosages on the other hand, say ,of two milligrams per kilogram of thisnew Examplel compound, produced excitationin mice (see Table IIIabove),.

and rather effectively antagonized the tranquilizing activity of orallysimultaneously administered 0.4 milligram doses of perphenazine. Thisnew compound also produced a significant hypotensive effect whenadministered intraperitoneally to unanesthetized normotensive rats.

Example 2 Example 3 N cyclohexyl-N-cyanoethyl-o-methoxybenzamide also.was produced in the manner described in Example 1 above and similarlytested as described therein and as shown in the above Tables I, II, andIII, and was shown to have both CNS depressant and blood pressuredepressor activity in dosages of 4 mg./ kg.

.Example 4 N-cyclohexyl-N-cyanoethyl-p-chlorobenzamide was also producedaccording to the process described for Example 1 above and similarlytested as'shown in Table I.

Oral doses of this compound of two milligrams per kilogram in propyleneglycol produced a high degree of excitation but its antagonism to 0.4milligram per kilogram doses of perphenazine was insignificant. Althoughdepression was the predominant symptom of animals receiving doses offour milligrams per kilogram of this new compound of Example 4, thedegree of reduction in spontaneous motor activity was less than that forthe compound of Example 1. It also was a blood pressure depressor asshown in Table II above.

Example 5 N-cyclohexyl N cyanoethyl-m-chlorobenzamide was also producedsimilar to the process described in Example 1, and it hadpharmacological effects similar to those for the compound of Example 2as shown in Table II. However, in smaller dosages, as shown in TableIII, it caused excitation during the first hour of measurement, but thespontaneous activity of mice receiving this reduced dos age rapidlydecreased during the next one and a half hour period.

Example 6 N-cyclohexyl-N-cyanoethyl-o-chlorobenzamide was producedaccording to the process described for Example 1 and was tested to haveproperties and an activity slightly less than the compound of Example 3.

Example 7 TABLET FORMULATION Gm./tablet Active ingredient 0.025 Lactose0.150 Sucrose 0.025 Corn starch 0.015 Stearic acid 0.003

These ingredients are granulated and compressed by standardpharmaceutical methods.

Example 8 CAPSULE FORMULATION Gm./capsule Active ingredient 0.025Magnesium stearate 0.002 Lactose, qs ad 0.300

These ingredients are screened, mixed and filled into hard gelatinecapsules.

Water for injection, USP, qs ad 100.00%.

While there is described above the principles of this invention inconnection with specific products, it is to be clearly understood thatthis description is made only by way of example and not as a limitationto the scope of this invention.

wherein A, B and C are selected from the group consisting of hydrogen,lower alkyl, lower alkoxy, and halogen, at least one of which is alkoxyor halogen, wherein x is a whole number from one to three, and wherein Ris cycloalkyl containing between three and seven carbon atoms.

2. A method according to claim 1 wherein A is hydrogen and B and C arelocated in the metaand para-positions.

3. A method according to claim 1 wherein x is 2.

4. A method according to claim 1 wherein R is cyclohexyl.

5. A method according to claim 1 wherein A is halogen and B and C arehydrogen.

6. A method according to claim 1 wherein A is methoxy and B and C arehydrogen.

7. A method according to claim 1 wherein said compound is N-cyclohexyl Ncyanoethyl-p-methoxybenzamide.

8. A method according to claim 1 wherein said compound is N-cyclohexyl Ncyanoethyl-m-methoxybenzamide.

9. A method according to claim 1 wherein said compound isN-cyclohexyl-N-cyanoethyl-p-chlorobenzamide.

10. A method according to claim 1 wherein the quantity of said compoundadministered is between about 0.5 and 10 milligrams per kilogram of thehost animal.

11. A method according to claim 1 wherein the quantity of said compoundadministered is between about 1 and 5 milligrams per kilogram of thehost animal.

12. A method according to claim 1 wherein said compound together with apharmaceutically acceptable carrier is administered in a unit dosecomposition in the form of a capsule, tablet, elixir or parenteralformulation.

13. A central nervous system depressant pharmaceutical compositioncomprising between about 10 and milligrams of a compound of the formula:

R wherein A is selected trom the group consisting of para and metamethoxy and ethoxy, wherein x is a whole number from one to three, andwherein R is selected from the group consisting of cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl together with apharmaceutically acceptable carrier.

14. A composition according to claim 13 wherein x is 2.

15. A composition according to claim 13 wherein R is cyclohexyl.

16. A composition according to claim 13 wherein said compound isN-cyclohexyl-N-cyanoethyl-p-methoxybenzamide.

17. A composition according to claim 13 wherein said compound isN-cyclohexyl-N-cyanoethyl-m-methoxybenzamide.

References Cited UNITED STATES PATENTS 2,927,126 3/1960 Pursglove260-465 D 3,457,294 7/1969 Crovetti et al. 260-465 D 3,172,869 3/1965Saxon 260465 D ALBERT T. MEYERS, Primary Examiner N. A. DREZIN,Assistant Examiner

